1. Field of the Invention
The present invention relates to a pharmaceutical composition and a method for preventing or treating a cardiovascular disease, the pharmaceutical composition including a (2′Z,3′E)-6-bromoindirubin-3′-oxime (BIO) compound or a pharmaceutically acceptable salt thereof as an active ingredient.
2. Discussion of Related Art
Myocardial infarction is a disease in which cardiac function declines due to apoptosis or necrosis of cardiomyocytes caused by shut off of the supply of oxygen and nutrients when blood flow is blocked due to main blood vessels of the heart being clogged. Since the apoptosis/necrosis of cardiomyocytes after myocardial infarction induces inflammation in tissues and causes a decline in contractile function of the heart muscle, as a compensatory mechanism, our bodies respond by promoting an inflow of macrophages to remove residual by-products of cardiomyocytes and inducing angiogenesis to resume the blood flow at the infarct sites. Also, to maintain the contractile function, cardiac fibroblasts proliferate and migrate to the infarct sites and then substitute for the sites where cardiomyocytes have been lost by forming an extracellular matrix. As a result, inflammatory responses in the heart tissues may be re-initiated, and a pump function of the heart may be declined.
It is known that the post-myocardial infarction death most frequently occurs within several hours of the onset of infarction, that is, approximately 50% of patients die within an hour, and approximately 80% of patients die within 24 hours. Therefore, early treatment of myocardial infarction is required, and the recurrence of the myocardial infarction needs to be prevented to reduce the long-term mortality and morbidity after the myocardial infarction.
As drugs for prevention and treatment of myocardial infarction, drugs such as aspirin, an antithrombotic drug, and the like have been known in the related art. However, aspirin has problems including allergy, drug tolerance, etc., and the antithrombotic drug has a risk of bleeding. Also, since the mortality surpasses 10% within one year after treatment of myocardial infarction and there are no other alternatives but to transplant a heart due to irreversible development into heart failure, a development of novel drugs having a potent therapeutic effect is needed.
Meanwhile, glycogen synthase kinase-3 (GSK-3) is a serine/threonine protein kinase that is composed of α and β isoforms encoded by separate genes and is known to be associated with a signaling pathway for regulating various cell functions. Since the abnormality in the pathway using GSK3 as a regulator is associated with the pathogenesis of diseases such as leukemia, diabetes, Alzheimer's disease, and neuropathy, an inhibitor targeting GSK3 to treat these diseases has been under an active development (Korean Registered Patent No. 10-1290509).
As a GSK3 inhibitor, a compound (2′Z,3′E)-6-bromoindirubin-3′-oxime (hereinafter referred to as a ‘BIO’ compound) is a compound that suppresses enzymatic activities of GSK3β which is an enzyme associated with glycogen metabolism and is reported to have effects on differentiation of stem cells, treatment of diabetes, and Alzheimer's disease. However, it remains to be revealed whether, in addition to proliferation of the cardiomyocytes, the functional/structural deterioration of infarct cardiac muscle may be improved under the control of pathological microenvironments, for example, improved by selectively inhibiting the proliferation of cardiac fibroblasts and suppressing an inflammatory phenotype of macrophages.